Project Summary The long-term goal of this work is to discover and understand the role of cellular long non-coding RNAs (lncRNAs) in CNS as well as peripheral reservoirs of HIV-1 replication. Human immunodeficiency virus type-1 (HIV-1) is a pathogenic retrovirus that is the causative agent of acquired immunodeficiency syndrome (AIDS) and its related disorders. For the three decades since the discovery of HIV-1, remarkable progress has been made in understanding the viral life cycle, host-virus interactions, prevention, and treatment of infection. Despite the success of ART, approximately ~ 2.6 million individuals are infected with HIV-1 every year in the world. Current antiretroviral therapies (ART) can successfully suppress HIV-1 to very low levels; however, these drugs are unable to completely eliminate virus from infected individuals making treatment a lifetime process. In addition, mutant viruses quickly evolve requiring change in therapeutic regimens, which lead to toxic and undesirable effects in patients. HIV-1-associated CNS disease remains a significant issue in the era of effective ART and a significant proportion of aviremic patients exhibit neurocognitive impairment. The mammalian genome encodes thousands of long noncoding RNAs (lncRNAs, >200 nucleotides), a class of RNAs increasingly recognized as playing major roles in gene regulation. Like coding mRNAs, lncRNAs are transcribed by RNA polymerase II, 5'-capped, spliced, and polyadenylated, but they lack protein-coding potential. Genomics studies have identified thousands of lncRNAs and intergenic lncRNA (lincRNAs) in the human and mouse genomes, but the vast majority has no known biological function. Recent studies have started to highlight the significance of lncRNAs in development, stem cell biology, and various disease states. Here, we propose to illuminate the roles and mechanisms of lncRNAs in HIV-1 replication and their potential significance in HIV-1 infected individuals. We will employ collaborative and multidisciplinary approaches to accomplish our goals. We have two broad specific aims: (1) Determine the role and function of cellular lncRNAs in regulating HIV-1 infection in primary macrophages, and evaluate the functional significance of these lnRNAs in HIV-1 infected individuals receiving ART. (2) Elucidate the molecular mechanisms by which cellular lncRNAs regulate viral pathogenesis. We will combine innovative approaches with state of the art facilities and a team of multidisciplinary collaborators to achieve our goals.